Preliminary studies of this laboratory have suggested that chronic hypoxia increases neuronal excitability and Na+ channel density in in vivo and in vitro immature neurons. The general hypothesis of this project is that chronic hypoxia increases neuronal excitability in immature rat neocortex via Na+ channel modulation. It is proposed that Na+ channel up-regulation is activated by neurotrophic factors via protein kinase pathways. Using electrophysiological, cellular and molecular approaches in in vivo preparations and in neuronal culture, the aims of this grant are to test the following specific hypotheses: i) chronic hypoxia enhances neuronal excitability and response to subsequent stress in the immature neocortical neurons but not in the adult ones; ii) chronic hypoxia induces an up-regulation of Na+ channel density in the immature neurons and this up-regulation plays a major role in increased susceptibility to subsequent stress; iii) Na+ channel up-regulation occurs at transcriptional and translational levels due to changes of specific extracellular and cytosolic factors such as neurotrophic factors and protein kinases.